1. Field of the Invention
This invention relates to bioerodible polymers containing a biologically active substance which is released when the polymer is brought into contact with a body fluid, thus releasing the biologically active material gradually and over a period of time. More particularly, this invention relates to such products in which the bioerodible polymer is sensitive to acidic media whereby control of the rate of erosion, and hence the rate of release of the biologically active substance can be controlled.
2. Description of the Prior Art
In U.S. Pat. No. 4,093,709 there are described bioerodible polymers intended to contain drugs for release as the polymer is eroded by contact with body fluids, such polymers being poly(ortho esters) or polycarbonates. A typical such polymer has the formula ##STR1## See also U.S. Pat. Nos. 4,131,648; 4,138,344 and 4,180,646.
Another class of bioerodible polymers suitable for the same purpose is described in U.S. Pat. No. 4,304,767 (the '767 Patent). These polymers are formed by a condensation reaction of a ketene acetal with a polyol and they have certain advantages over those of the U.S. Pat. No. 4,093,709, such as the fact that their production is not accompanied by the formation of low molecular weight by-products such as alcohol and the reaction proceeds rapidly and at ambient temperature. The absence of formation of small molecular weight by-products enables one to produce dense crosslinked materials incorporating a drug.
It has been proposed to employ bioerodible polymers for the gradual release of drugs, such polymers being sensitive to the pH of the ambient medium. See, for example, a paper by Heller et al. in the Journal of Applied Polymer Science, Vol. 22, pp. 1991-2009 (1978). These polymers are partial esters of methyl vinyl ether-maleic anhydride copolymers which have been reacted with alcohols to form polymers that contain both carboxylic acid and carboxylic ester functionalities.
In these polymers, the size of the alkyl group in the ester functionality determines the rate at which the polymer erodes at a constant external pH. Most importantly, any particular polymer exhibits a very pronounced dependence of erosion on the external pH and even very small changes in this external pH have a very large effect on rate of polymer erosion.
An approach to utilizing this methodology is described in a paper by Heller and Trescony in Journal of Pharmaceutical Sciences, Vol. 68, pp. 919-921 (1979). A polymer similar to those of the cited Heller and Trescony paper containing a drug is coated with a hydrogel containing urease. When exposed to a solution containing urea, the urease in the hydrogel acts on the urea, which infuses into the hydrogel, thus releasing ammonium bicarbonate and ammonium hydroxide. This accelerates erosion of the bioerodible polymer and hence accelerates release of the drug, e.g., hydrocortisone.